Sparingly soluble salts of the 6, 6-ureylene-bis-(1-methylquinolinium) cation



United States Patent Ofitice 3,312,707

Patented Apr. 4, 1967 3 312 707 According to a further feature of the invention I SPAR G SQLLIBIE SALTS OF THE provide pharmaceutical compositions suitable for the UREYLENE BIS 1 METHYLQUIN prophylactic treatment of babesiasis in cattle which com- LINIUM) CATION prise as active ingredient one of the said salts or complexes William Glynne Moss Jones, Macclesfield, England, as- 5 of this invention in admixture with a diluent or carrier signor to Imperial Chemical Industries Limited, Lontherefor. @1011, l a P Of Great Britain The said compositions are preferably those suitable for N 'Q P Fllfid 9 g 323,171 parenteral administration for example sterile aqueous or Claims priority, application Great Britain, Dec. 20, 1962 oily suspensions or dispersible powders from which aque- 4 C]aim;l8, (%1l/62260 2s6) 10 ous suspensions can be prepared. The said suspensions may conveniently contain wetting agents, dispersing agents This invention relates to heterocyclic compounds and or suspending agents, more particularly it relates to quinoline derivatives which The invention is illustrated but not limited by the folare salts or complexes, sparingly soluble in water, and lowing examples in which the parts are by weight: which are useful for prophylactic treatment against 1 babesiasis in cattle. Example 1 According to the invention I provide quinoline derivatives which are salts or complexes formed by interaction Q E of Parts 6,6 y y f a 6,6 urey1ene bis (l methylquinolinium) cation f the quinolinium methosulphate) in 100 parts of water is added f m l to a solution of 14.4 parts of 5,5'-methylene-b1s salicylic acid in 200 parts of 2% aqueous sodium hydroxide solu- NHOONH tion. The reaction mixture is filtered, the solid residue is washed with water and is then dried at 18-22 C. There is thus obtained 6,6-ureylene-bis-(1-methylquin0linium)- N( (5,5-methylene-bis salicylate) as a yellow crystalline solid CH3 CH3 melting with decomposition at 220 C. and a 5,5'-methylene-bis salicylate (I), a 1,1'-methylene- Exam l8 2 bis-(2-hydroxy-3-naphthoate) (II) or a syrn.-bis-(m-amip HOPBBZOYI amino P methyl benzoyl napthyl' 9.7 parts of 1,1-rnethylene-bis-(2-hydroxy-3-naphthoic ammo-4,6,s'msulphonate)Carbamlde (HI) amon of the acid) [also known as embonic acid and pamoic acid] are formula? dissolved in 50 parts of 4% aqueous sodium hydroxide solution. To this solution is added a solution of 14 parts HO- OH of 6,6 ureylene bis (1 methylquinolinium methosull phate) in 100 parts of water. The reaction mixture is fil- CH tered and the solid residue is Washed with water and dried (D at 18-22 C. There is thus obtained 6,6'-ureylene-bis-(1- methylquinolinium) 1,1 methylene bis 2 hydroxy- -ooo OH OH 000- 3-naphth0ate) as a yellow crystalline solid, melting with decomposition at 226 C.

The parts of 4% aqueous sodium hydroxide used in the above process is replaced by 50 parts of 5.6% Q aqueous potassium hydroxide or by 50 parts of 1.7% aqueous ammonia and there is likewise obtained the desired pro-duct, melting with decomposition at 226 C.

III) According to a further feature of the invention I pro- Example 3 vide a process for the manufacture of the said salts or complexes which comprises interaction of the said cation and the said anion in an aqueous medium.

The salts or complexes with which the invention is concerned are sparingly-soluble in water and they are thus precipitated from the reaction medium. As a suitable salt containing the said cation there may be mentioned for A solution of 10 parts of 6,6'-ureylene-bis-(l-methylquinolinium methosulphate) in 190 parts of water is added to a solution of 13.7 parts of hexasodium sym.-bis- (m-aminobenzoyl m amino p methylbenzoyl-l naphthylamino 4,6,8-tri-sulphonate) carbamide (also example the methosulphate and as a suitable salt containknown as amifl Sodium) in Pi f i The ing the said anion there may be mentioned f example reaction mixture is filtered and the solid resldue is washed an alkaline metal salt for example a sodium or potassium With Water and dried at There 15 thus obtained salt, or an ammonium salt. The reactionmay be carried y y q nlum)-Suram1nate as out in water as the aqueous medium. a yellow powder melting with decomposition at 300 C.

' 3 Example 4 5 parts of 6,6'-ureylene-bis-(1-methylquinolinium)- (5,5'-methylene-bis salicylate) and 48 parts of a 0.1% aqueous solution of polyoxyethylene sorbitan mono-oleate are milled for 1 hour. There is thus obtained an aqueous suspension of 6,6'-ureylene-bis-( l-methylquinolinium (5, 5'-methylene-bis salicylate) which is suitable for parenteral use for the prophylactic treatment of babesiasis in domestic animals. I

Example 5 2.5 parts of 6,6'-ureylene-bis-(1-methylquinolinium)- suraminate and 24 parts of a 0.1% aqueous solution of polyoxyethylene sorbitan mono-oleate are ball-milled for 30 minutes. There is thus obtained an aqueous suspension which is suitable for parenteral use for the prophylactic treatment of babesiasis in domestic animals.

Example 6 5 parts of 6,6'-ureylene-bis-(1-methylquinolinium)- (1,1' methylenebis-2-hydroxy-3naphthoate) and 47.5 parts of a 0.1% aqueous solution of polyoxyethylene sorbitan mono-oleate are ball-milled for 30 minutes. There is thus obtained an aqueous suspension of 6,6- ureylene-bis-( l-methylquinolinium) (1,1'-methylene-bis- 2-hydroXy-3-naphthoate) which is suitable for parenteral use for the prophylactic treatment of babesiasis in domestic animals.

Example 7 20 parts of 6,6'-ureylene-bis-(1-methylquino1iniurn)- (5,5'-methylene-bis salicylate) and 80 parts of arachis oil are ball-milled for 3 hours. There is thus obtained an oily suspension of 6,6-ureylene-bis-(l-methylquinolinium)-(5,5'-rnethylene-bis salicylate) which is suitable for parenteral use for the prophylactic treatment of babesiasis in domestic animals.

CH3 CH3 with an anion selected from the group consisting of the 5,5'-methylene-bissalicylate anion of the formula HO OH "O O C- CH2 C O 0* the 1,1-methy1ene-bis-(2-hydroXy-3-naphthoate) anion of the formula 'OOCII (1)11 OH COO" and the sym.-bis (m-aminobenzoyl-m-aminop-methylbenzoyl 1 naphthylamino-4,6,8trisulphonate)carbamide anion of the formula Example 8 100 parts of 6,6-ureylene-bis-(1-methylquinolinium)- (1,1' methylene bis 2 hydroXy-3-naphthoate) are triturated with 70 parts of a solution prepared by dissolving 25 parts of soya-bean lecithin and 5 parts of a condensation product (obtained from octyl cresol and 8-10 molecular proportions of ethylene oxide) in 700 parts of diethyl ether. The paste is stirred until all the ether has evaporated and the resultant solid is then ground in a suitable mill. There is thus obtained a dispersible powder and on addition of water, there is obtained an aqueous suspension of 6,6'-ureylene-bis-(1-methylquinolinium)- (1,1' methylene-bis-Z-hydroxy-3naphthoate) which is suitable for parenteral injection for the prophylactic treatment of babesiasis in domestic animals.

Example 9 97 parts of embonic acid are dissolved in 1.5 litres of water containing sufficient sodium hydroxide to give a solution of sodium embonate of pH 10.0 which is then filtered; with vigorous agitation, the filtrate is adjusted to pH 7.0. 142 parts of 6,6'-ureylene-bis-(l-methylquinolinium methosulphate') are dissolved in 1.5 litres'of water and the solution is filtered. To this filtrate is added the solution of sodium embonate with vigorous agitation l S03- S03" NHCONH- 2. 6,6 ureylene-bis-(l-methylquinolinium)-5,5'-methylene-bis-salicylate.

3. 6,6 ureylene-bis-(l-methylquinolinium)embonate.

4. 6,6 ureylene bis (l-methylquinolinium)suraminate.

References Cited by the Examiner UNITED STATES PATENTS 2,108,484 2/1938 Hamer et al. 260286 X 2,662,083 12/1953 Eastland et al. 260286 2,760,964 8/ 1956 Carrington et al 260-286 2,827,466 3/1958 Slack et al 2 60313 2,901,484 8/1959 Schock 260-286 2,925,417 2/1960 Elslager et al 260240 3,022,218 2/ 1962 Sherman et a1 16753 3,152,042 10/1964 Wood et al. 167-53 3,200,143 8/1965 Copp 260501 FOREIGN PATENTS 703,484 2/ 1954 Great Britain. 839,505 6/ 1960 Great Britain.

ALEX MAZEL, Primary Examiner.

DONALD G. DAUS, Assistant Examiner. 

1. A SALT OF THE 6,6-UREYLENE-BIS-(1-METHYLQUINOLINIUM) CATION OF THE FORMULA 